Project Summary Currently, abuse of prescription opioid analgesics and heroin is a pervasive problem in the U.S. Although several medications, including methadone, buprenorphine, and naltrexone, are available and effective in treating opioid use disorder (OUD), long-term relapse rates remain high. The current studies are designed to examine a novel approach to treating OUD, namely use of a vaccine (OXY-KLH) targeted against oxycodone, one of the most commonly abused prescription opioids, and a vaccine (M-KLH) targeted against heroin/morphine. Ultimately, a bivalent vaccine (OXY-KLH and M-KLH) will be developed that will target oxycodone and heroin. The long-term goal of this research is to develop a multivalent vaccine directed against oxycodone, heroin, and other relevant opioids. However, during our pre-IND meeting, the FDA/CBER asked that we study each vaccine separately before moving forward with development of the bivalent vaccine. The current application proposes a Phase 1a/1b study designed to evaluate the safety (Aim 1), immunogenicity (Aim 2), and preliminary efficacy (Aim 3) of OXY-KLH during the UG3 phase of the grant period (Study 1) and a similar Phase 1a/1b study of M-KLH during the UH3 phase of the grant period (Study 2). Transition to the UH3 phase will be determined after safety, immunogenicity, and preliminary efficacy analyses have been performed for the OXY-KLH vaccine. Overall, the proposed studies will provide a great deal of information about the safety and potential efficacy of the vaccines in reducing the abuse liability of opioids, which will be administered in a controlled laboratory setting. If the outcomes of the proposed studies with OXY-KLH and M- KLH are favorable, we will proceed with development of the bivalent vaccine (OXY-KLH plus M-KLH).